Increasingly there is a need for effective treatments for nervous system disorders and neurological deficiencies. Many of these diseases correlate with increasing age due mainly to degenerative changes in the nervous systems. Although in early stages of some diseases, certain systems are specifically affected (e.g., cholinergic systems in Alzheimer's Disease and Myasthenia Gravis, the dopaminergic system in Parkinson's Disease), multiple neurotransmitter system deficiencies (acetylcholine, dopamine, norepinephrine, serotonin) are generally found at later stages of disease such as senile dementia, multi-infarct dementia, Huntington's Disease, and mental retardation. This explains the generally observed multiple symptomatology that includes cognitive, neurological, and effective/psychotic components (See, e.g., Gottfries, Psychopharmacol., 1985, 86, 245). Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment (See, e.g., Francis, et al., New England J. Med., 1985, 7, 313) whereas neurological deficits (e.g. Parkinsonian symptoms) and mood/mental changes may be related to impairment of dopaminergic and serotonergic systems, respectively. Other neurological deficits (e.g. Myasthenia Gravis) are related to cholinergic deficiencies in the peripheral nervous system.
Treatment strategies employed previously encompass vasoactive drugs like vincamine and pentoxifylline; metabolic enhancers like ergoloid mesylates, piracetam, and naftidrofuryl; neurotransmitter precursors like 1-DOPA, choline, and 5-hydroxytryptamine; transmitter metabolizing enzyme inhibitors such as physostigmine; and neuropeptides like adrenocorticotropic hormone and vasopressin-related peptides. Except for 1-DOPA treatment for Parkinson's Disease and cholinesterase inhibitor treatment for Myasthenia Gravis, these treatment strategies have generally failed to enhance the residual function of the affected systems by enhancing the stimulus-induced release of neurotransmitters. Theoretically, such an enhancement would improve the signal-to noise ratio during chemical transmission of information, thereby reducing deficits in processes related to cognition, neurological function, and mood regulation.
It is known that certain polycyclic compounds enhance the stimulus-induced release of neurotransmitters, specifically acetylcholine in nervous tissues, and thus improve processes involved in learning and memorization of an active avoidance task. For example, European Patent Application 311,010, published Apr. 12, 1989, and U.S. Pat. No. 5,173,489 issued Dec. 22, 1992 discloses the utility as cognition enhancers of .alpha.,.alpha.-disubstituted aromatics or heteroaromatics having the formula: ##STR2## wherein X and Y are taken together to form a saturated or unsaturated carbocyclic or heterocyclic first ring and the shown carbon in said ring is .alpha. to at least one additional aromatic ring or heteroaromatic ring fused to the first ring, one of Het.sup.1 or Het.sup.2 is 2, 3, or 4-pyridyl; or 2, 4, or 5-pyrimidinyl, and the other is selected from:
(a) 2, 3, or 4-pyridyl PA1 (b) 2, 4, or 5-pyrimidinyl PA1 (c) 2-pyrazinyl PA1 (d) 3 or 4-pyridazinyl, PA1 (e) 3 or 4-pyrazolyl, PA1 (f) 2 or 3 -tetrahydrofuranyl, and PA1 (g) 3-thienyl. PA1 R.sub.2 and R.sub.3 are independently H, F, Cl, Br, NO.sub.2, CONH.sub.2, CON(R.sub.4)(R.sub.4 '), S(O).sub.m R.sub.4, CF.sub.3, or N(R.sub.4)(R.sub.4 '); PA1 R.sub.4 and R.sub.4 ' are independently H, alkyl having from 1 to about 4 carbon atoms, CH.sub.2 Phe--W, or Phe--W; PA1 Phe is a phenyl group; PA1 R.sub.5 is --(CH.sub.2).sub.n --Y or --OCOR.sub.4 ; PA1 Y is H, OH, NH.sub.2, NHR.sub.4, N(R.sub.4)(R.sub.4 '), NHCOR.sub.4, NHCO.sub.2 R.sub.4, NHS(O).sub.2 R.sub.4, F, Cl, Br, OR.sub.4, S(O).sub.m R.sub.4, CO.sub.2 H, CO.sub.2 R.sub.4, CN, CON(R.sub.4)(R.sub.4 '), CONHR.sub.4, CONH.sub.2, COR.sub.4, Phe, Phe--W, --C.tbd.CCO.sub.2 R.sub.4, --CH.dbd.CHR.sub.4, --C.tbd.CR.sub.4, or a heterocyclic aromatic moiety such as a 4-pyridyl, 2-pyridyl, 4-pyrimidyl, or pyrazinyl group; PA1 W is F, Cl, Br, R.sub.4, OR.sub.4, NO.sub.2, NH.sub.2, NHR.sub.4, N(R.sub.4)(R.sub.4 '), CN, or S(O).sub.m R.sub.4 ; PA1 m is 1 or 2; and PA1 n is 1-7.